The expanding HIV-1 pandemic, and the failure of human efficacy trials of T-cell and antibody-based vaccines, highlight the major gaps in knowledge that must be filled in order to pursue rational HIV-1 vaccine design and development. One of the most important knowiedge gaps relates to the precise nature of early virus-host interactions that lead to virus transmission and productive clinical infection. This application is a new HIVRAD proposal by investigators whose recent scientific discoveries relate directly to this priority area of research. These discoveries - the identification of transmitted/founder HIV-1 and SIV genomes (Keele 2008;Keele 2009;Salazar 2009), the identification of genetically-divergent SIVsmm strains in naturallyinfected sooty mangabeys (Apetrei 2005;Apetrei 2007), and the identification of innate mucosal immune responses modulating early virus-host interactions (Estes 2006;Estes 2008;Li 2009) - create a unique and timely opportunity to focus three cutting edge research themes on a high priority HIV/SIV vaccine research problem. The current proposal is comprised of three interrelated projects and two cores led by investigators at the University of Alabama at Birmingham (Shaw and Hahn);the University of Pittsburgh (Apetrei and Pandrea);and NCI-Frederick (Estes, Keele and Lifson). Project #1 is "Mucosal transmission and pathogenicity of novel SIVsmm virus strains (Apetrei)." Project #2 is "Identification, cloning and characterization of transmitted/founder SIVsmm (Hahn)." Project #3 is "Molecular analysis of the mucosal SIVsmm transmission bottleneck (Shaw)." Collectively, the projects will test this hypothesis: Identification, molecular cloning, and in vivo analysis of naturally-occurring mucosally-transmitted strains of SIVsmm corresponding to transmitted/founder viruses will reveal viral-host interactions responsible for selective SIV transmission across rectal, vaginal and cervical mucosa and will provide novel, genetically-divergent, pathogenic virus challenge strains for vaccine testing. A key deliverable of this research to the SIV/HIV vaccine field, in addition to new scientific insights into mucosal transmission, will be 18 molecular clones of transmitted/founder viruses representing three widely divergent SIVsmm genetic lineages for use as potential challenge stocks.

Public Health Relevance

The expanding HIV-1 pandemic, and the failure of human clinical trials of T-cell and antibody-based vaccines, highlight gaps in scientific knowledge about the initial steps in virus transmission and vaccine approaches to prevent infection. This project will identify and clone new, naturally occurring strains of SIVsmm and will use these to elucidate early infection events in the SIV-rhesus macaque model of human HIV-1 infection.